Increasing evidence indicates that alcohol consumption adversely affects immune function, and may increase the likelihood of HIV transmission and progression to disease. There is a clear association between alcohol use and the risk of contracting HIV infection, yet it remains to be determined whether this is due to immunologic or behavioral mechanisms. Although studies in humans are limited, alcohol has been shown to markedly affect cell-mediated and humoral immune responses. Moreover, consumption of even small amounts of alcohol by humans has been shown to increase HIV replication and affect the production of certain cytokines in cells obtained after alcohol consumption. Alcohol use also causes marked changes in gastrointestinal structure and function, and may adversely affect mucosal immune responses. Since the gastrointestinal tract has recently been shown to be important in the transmission and pathogenesis of AIDS, examining mucosal immune responses during alcohol consumption is crucial for determining the effects of alcohol as a cofactor in transmission and disease progression. We hypothesize that chronic alcohol use; 1) results in an increase in viral target cells specifically in the intestinal tract, resulting in increased susceptibility to infection, and increased viral loads in primary SIV infection, and; 2) results in increased turnover of viral target cells in the intestinal tract, resulting in sustained local viral replication, and an increased rate of disease progression. The Specific Aims of this proposal are: 1) To determine whether chronic alcohol consumption results in an increased rate of mucosal SIV transmission. This will be accomplished by chronically administering alcohol to macaques, and comparing their susceptibility to an atraumatic, intrarectal, low-dose inoculation of SIVmac251, with that of non-alcohol consuming controls. 2) To compare the cellular and molecular changes in the peripheral and mucosal lymphoid tissues of macaques receiving alcohol to those that are not, both before and after SIV infection. Alcohol will be administered to groups of macaques and cells from multiple peripheral and mucosal lymphoid tissues will be serially examined before and during SIV infection. Changes in viral target cells, naive and memory T cell immunophenotyping, chemokine receptor expression, cytokine and SIV-specific cytotoxic T cell (CTL) production, and levels of cellular activation and proliferation will be analyzed in these tissues by various state-of the-art techniques, and compared with viral loads in plasma and tissues by quantitative methods.